Cardiovascular activity of A-74283, a 5-hydroxytryptamine 1A agent, in the spontaneously hypertensive rat.
A-74283, (+,-)trans-2-(4-(3a,4,4a,6a,7,7a-hexahydro-4,7-etheno-1 H cyclobut [f] isoindol-1,3-dionyl)-butyl)-9-methoxy-2,2,2a,4,5,9b-hexahydr o-1 H-benz[e]isoindol HC1, was studied in receptor binding assays and in the spontaneously hypertensive rat (SHR). In radioligand binding to rat cortex, A-74283 had high affinity (equipotent to 8-OH-DPAT) and high selectivity for 5HT1A receptors compared to 5HT1B sites. In conscious SHR, A-74283 lowered mean arterial pressure (MAP) in a dose-related fashion with a prolonged effect after oral administration of higher doses, but heart rate (HR) was not changed. In anesthetized SHR, i.v. administration of A-74283 decreased MAP and total peripheral resistance, but not cardiac output. Pretreatment of conscious SHR with the selective 5TH1A receptor antagonists spiroxatrine or BMY 7378 reduced the hypotensive effect of A-74283 significantly, but pretreatment with adrenergic antagonists phenoxybenzamine or idazoxan or the 5HT2 receptor blocker ketanserin did not alter the effect of A-74283. Intracisternal administration of A-74283 also decreased MAP; however, A-74283 had no effect on blood pressure in pithed SHR in which blood pressure was supported with vasopressin, in contrast to nitroprusside. These data demonstrate that A-74283 exerts a potent hypotensive effect in SHR via systemic vasodilation originating from a central 5HT1A receptor mechanism. A-74283 may be useful for studying 5HT1A receptors and cardiovascular function.
Lee
J Y
JY
Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, IL, USA. leej@randb.abbott.com
Hancock
A A
AA
Warner
R B
RB
Brune
M E
ME
Meyer
M D
MD
DeBernardis
J F
JF
D018674:Adrenergic Antagonists / Q000627:therapeutic use; D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D002946:Cisterna Magna; D003655:Decerebrate State; D004353:Drug Evaluation, Preclinical; D006439:Hemodynamics / Q000187:drug effects*; D006973:Hypertension / Q000188:drug therapy*; D007211:Indoles / Q000627:therapeutic use*; D054833:Isoindoles; D007650:Ketanserin / Q000494:pharmacology; D008297:Male; D009599:Nitroprusside / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D011918:Rats, Inbred SHR; D018490:Serotonin Agents / Q000627:therapeutic use*; D012702:Serotonin Antagonists / Q000627:therapeutic use
C110717:A 74283; D018674:Adrenergic Antagonists; D000959:Antihypertensive Agents; D007211:Indoles; D054833:Isoindoles; D018490:Serotonin Agents; D012702:Serotonin Antagonists; D009599:Nitroprusside; D007650:Ketanserin